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The International Journal of Biochemistry & Cell Biology 37 (2005) 19741984

Review

Skeletal muscle hypertrophy and atrophy signaling pathways


David J. Glass
Regeneron Pharmaceuticals, 777 Old Saw Mill River Road, Tarrytown, NY 10591-6707, USA Received 12 December 2004; received in revised form 26 March 2005; accepted 12 April 2005

Abstract Skeletal muscle hypertrophy is dened as an increase in muscle mass, which in the adult animal comes as a result of an increase in the size, as opposed to the number, of pre-existing skeletal muscle bers. The protein growth factor insulin-like growth factor 1 (IGF-1) has been demonstrated to be sufcient to induce skeletal muscle hypertrophy. Over the past few years, signaling pathways which are activated by IGF-1, and which are responsible for regulating protein synthesis pathways, have been dened. More recently, it has been show that IGF-1 can also block the transcriptional upregulation of key mediators of skeletal muscle atrophy, the ubiquitin-ligases MuRF1 and MAFbx (also called Atrogin-1). Further, it has been demonstrated recently that activation of the NF- B transcription pathway, activated by cachectic factors such as TNF , is sufcient to induce skeletal muscle atrophy, and this atrophy occurs in part via NF- B-mediated upregulation of MuRF1. Further work has demonstrated a trigger for MAFbx expression upon treatment with TNF the p38 MAPK pathway. This review will focus on the recent progress in the understanding of molecular signalling, which governs skeletal muscle atrophy and hypertrophy, and the known instances of cross-regulation between the two systems. 2005 Elsevier Ltd. All rights reserved.
Keywords: Hypertrophy; Atrophy; IGF-1; Phosphatidylinositol-3 kinase (PI3K); Akt; mTOR; Rapamycin; GSK3beta; Ubiquitin ligase; Proteasome; MuRF1; MAFbx; Atrogin

Contents 1. 2. 3. 4. 5. 6. 7. 8. Protein synthesis pathways downstream of IGF-1 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Hypertrophy mediators downstream of PI3K and Akt: the Akt/mTOR pathway . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . A second hypertrophy mediator downstream of PI3K and Akt: GSK3 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Skeletal muscle atrophy occurs in part via induction of distinct E3 ubiquitin ligases . . . . . . . . . . . . . . . . . . . . . . . . . . . . Akt inhibition of FOXO transcription factors blocks upregulation of MuRF1 and MAFbx . . . . . . . . . . . . . . . . . . . . . . mTOR blocks upregulation of MuRF1 and MAFbx . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Triggers of atrophy: the NF- B pathway and p38 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1975 1975 1976 1977 1978 1979 1979 1980 1981 1981

E-mail address: david.glass@regeneron.com. 1357-2725/$ see front matter 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.biocel.2005.04.018

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1. Protein synthesis pathways downstream of IGF-1 An increase in weight-bearing by a muscle, as seen in models of muscle hypertrophy such as compensatory hypertrophy as well as agents that induce hypertrophy such as IGF-1, induce an increase in muscle mass by stimulating the phosphatidylinositol-3 kinase (PI3K)/Akt pathway, resulting in the downstream activation of targets which are required for protein synthesis (Bodine, Stitt, et al., 2001; Rommel et al., 2001) (Fig. 1). Overload-induced muscle hypertrophy may lead to activation of the PI3K/Akt pathway by directly inducing muscle expression of IGF-1 (DeVol, Rotwein, Sadow, Novakofski, & Bechtel, 1990), which is sufcient to induce hypertrophy of skeletal muscle (Vandenburgh, Karlisch, Shansky, & Feldstein, 1991), as was demonstrated in transgenic

mice in which IGF-1 is overexpressed in skeletal muscle (Coleman et al., 1995; Musaro et al., 2001). Recently, it was demonstrated that activation of Akt was sufcient to induce hypertrophy in vivo, by the production of transgenic mice in which a mutant, constitutively active, form of Akt is conditionally expressed in adult skeletal muscle (Lai et al., 2004). In that setting, acute activation of Akt, for 23 weeks, is sufcient to induce dramatic increases in the size of skeletal muscle; this increase occurs via an increase in the average cross-sectional area of individual muscle bers by more than two-fold, caused by an increase in activation of protein synthesis pathways (Lai et al., 2004). Conversely, settings of skeletal muscle atrophy, such as burn, are coupled with a decreased ability to activate the Akt pathway (Sugita et al., 2005). Further, atrophy settings such as sepsis cause a decrease in protein synthesis, and an increase in atrophy, which can be attenuated by giving IGF-1 (Svanberg et al., 2000).

2. Hypertrophy mediators downstream of PI3K and Akt: the Akt/mTOR pathway Experiments in Drosophila helped to dene a pathway downstream of PI3K and Akt, which can control cell size (Fig. 1). Negative genetic perturbations of IRS-1 (Bohni et al., 1999), PI3K (Leevers, Weinkove, MacDougall, Hafen, & Watereld, 1996), the Drosophila homolog of the mammalian target of rapamycin (mTOR, also known as FRAP or RAFT-1) (Zhang, Stallock, Ng, Reinhard, & Neufeld, 2000) as well as of p70S6 Kinase (Montagne et al., 1999) (p70S6K) each resulted in decreases in cell size. Although IGF-1 activates mTOR and p70S6K downstream of PI3K/Akt activation; amino acids can activate mTOR directly, causing a subsequent stimulation of p70S6K activity (Burnett, Barrow, Cohen, Snyder, & Sabatini, 1998; Hara et al., 1998). Thus, mTOR appears to have an important and central function in integrating a variety of growth signals, from simple nutritional stimulation to activation by protein growth factors, resulting in protein synthesis. Rapamycin is a pharmacologic agent which binds to mTOR, and inhibits its function (Pallafacchina, Calabria, Serrano, Kalhovde, & Schiafno, 2002). In vitro, when applied to myotube cultures, rapamycin blocks activation of p70S6K downstream of either

Fig. 1. Hypertrophy signaling dominantly regulates atrophy signaling. On the left, the IGF-1 signaling pathways relevant to hypertrophy are presented. Signaling molecules, which have been shown to have a negative effect on hypertrophy are colored red. Proteins whose activation induces hypertrophy are shown in green. Selected abbreviations: GSK3 , glycogen synthase kinase 3 beta; mTOR, mammalian target of rapamycin; PI3K, phosphatidylinositol-3 kinase. On the right, signaling pathways relevant to atrophy are illustrated. Multiple different perturbations can induce skeletal muscle atrophy pictured is TNFalpha signaling, since it induces NF- B a transcription factor whose activation is required for maximal atrophy. NF- B activation is the trigger, which induces transcriptional upregulation of the E3 ubiquitin-ligase MuRF1. A second ligase, MAFbx, is also upregulated in all physiologic settings of atrophy studied; its trigger is the MAPK p38. Activation of Akt inhibits the transcriptional upregulation of MAFbx and MuRF1, via the inhibtion of the FOXO family of transcriptional factors, and also via a second mechanism downstream of mTOR.

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activated Akt or IGF-1 stimulation (Pallafacchina et al., 2002; Rommel et al., 1999, 2001) (Fig. 1). Genetic support for a linear Akt/mTOR/p70S6K pathway came from reports which demonstrated that the tuberous sclerosis complex-1 and -2 proteins (Tsc1 and Tsc2) can inhibit mTOR. Akt phosphorylates Tsc2, thereby activating mTOR at least in part by disrupting the Tsc1Tsc2 complex (Inoki, Li, Zhu, Wu, & Guan, 2002). Furthermore, in insulin or serum-stimulated cells, activation of p70S6K is inhibited by expression of the Tsc1Tsc2 complex (Inoki et al., 2002; Tee et al., 2002). This nding demonstrates that introduction of a genetic inhibitor of mTOR, downstream of Akt, inhibits the activation of p70S6K, adding genetic evidence for an Akt/mTOR/p70S6K pathway. Since PDK1 has been shown to phosphorylate p70S6 kinase directly (Pullen et al., 1998), one might have assumed that activation of mTOR was dispensable in some settings of p70S6K activation. That might still be the case; alternatively, it may be that p70S6K must rst be primed by another kinase, such as mTOR, before being activated by PDK1 (Hannan, Thomas, & Pearson, 2003; Saitoh et al., 2002). Activation of p70S6 kinase is necessary for muscle bers to achieve normal size, since skeletal muscle cells are smaller when they are null for the gene (Ohanna et al., 2005). In addition to stimulating p70S6 kinase, activation of mTOR inhibits PHAS-1 (also known as 4E-BP), which is a negative regulator of the protein initiation factor eIF-4E (Hara et al., 1997; Proud, 2004). PHAS-1 can directly bind a protein called raptor, which also binds mTOR (Hara et al., 2002; Kim do et al., 2002). Mutations in PHAS-1, which inhibit interaction with raptor also inhibit mTOR-mediated phosphorylation of PHAS-1 (Choi, McMahon, & Lawrence, 2003). Finally, overexpression of raptor can enhance the phosphorylation of PHAS-1 by mTOR in vitro (Choi et al., 2003; Schalm, Fingar, Sabatini, & Blenis, 2003). mTOR binds PHAS-1 by a TOR signaling (TOS) motif; this same motif is found in p70S6K (Schalm et al., 2003), demonstrating both a mechanism for mTORs interaction with its downstream signaling components, and the possibility that there may be some selective hierarchy in signaling (since the same motif binds mTOR, one might wonder if there is competition for the same mTOR interaction site). mTOR can increase protein synthesis in skeletal muscle by modulating at least two distinct pathways,

the p70S6K pathway and the PHAS-1 pathway (Fig. 1). Blockade of PHAS-1 might be a potential route to increasing protein synthesis, and therefore hypertrophy. Stimulation of p70S6K might be a second route, since muscle cells are smaller when p70S6K is absent (Ohanna et al., 2005). Interestingly, the mTOR pathway may also be important for signaling to eIF2B, a translation initiation factor (Kubica, Bolster, Farrell, Kimball, & Jefferson, 2005). When rats were subjected to exercise, eIF2B protein increased however, this increase was blocked by the mTOR-inhibitor rapamycin (Kubica et al., 2005). This nding seemingly reconnects distinct Akt signaling pathways, the Akt/GSK3/eIF2B pathway, and the Akt/mTOR/p70S6K pathway (Kubica et al., 2005).

3. A second hypertrophy mediator downstream of PI3K and Akt: GSK3 Glycogen synthase kinase 3 beta, GSK3 , is a distinct substrate of Akt that has been shown to modulate hypertrophy. GSK3 activity is inhibited by Akt phosphorylation (Cross, Alessi, Cohen, Andjelkovich, & Hemmings, 1995). Expression of a dominant negative, kinase inactive form of GSK3 -induces dramatic hypertrophy in skeletal myotubes (Rommel et al., 2001), as does pharmacologic inhibition of GSK3 (Vyas, Spangenburg, Abraha, Childs, & Booth, 2002). In cardiac hypertrophy, GSK3 phosphorylation is also evident (Hardt & Sadoshima, 2002) and expression of a dominant negative form of GSK3 can induce cardiac hypertrophy (Hardt & Sadoshima, 2002). Similarly to skeletal muscle hypertrophy, cardiac myocyte hypertrophy was shown to proceed via a PI3K dependent process, linking GSK3 to the PI3K/Akt pathway in the heart (Haq et al., 2000). GSK3 blocks protein translation initiated by the eIF2B protein (Hardt & Sadoshima, 2002). Therefore, GSK3 inhibition may induce hypertrophy by stimulating protein synthesis independent of the mTOR pathway. Additional evidence for this idea was provided by a study using the GSK3 inhibitor Wnt1. Wnt proteins are secreted ligands, which bind to distinct Frizzled receptors (Kawano & Kypta, 2003; Veeman, Axelrod, & Moon, 2003). Activation of the Wnt/Frizzled pathway is a unique means of phosphorylating, and thereby inhibiting GSK3

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(Beals, Sheridan, Turck, Gardner, & Crabtree, 1997; Diaz-Benjumea & Cohen, 1994). Application of Wnt to skeletal myotubes in vitro resulted in a phenotype resembling hypertrophy, via phosphorylation of GSK3 (Rochat et al., 2004). It should be noted, however, that the myotubes treated with Wnt demonstrated greater nuclei/myotube, suggesting the alternate possibility that the phenotype seen came as a result of enhanced differentiation (Rochat et al., 2004). It remains to be formally shown whether inhibiting GSK3 blockade of the protein initiation factor eIF2B is sufcient to induce hypertrophy, however, eIF2B has been implicated as important in the increase in protein synthesis induced by resistance exercise (Kubica et al., 2005).

4. Skeletal muscle atrophy occurs in part via induction of distinct E3 ubiquitin ligases One might wonder whether skeletal muscle atrophy might simply be the converse of hypertrophy. Indeed, the hypertrophy-inducing Akt protein synthesis pathways have been shown to be inhibited in a burn model of atrophy (Sugita et al., 2005), and there is a distinct set of genes, which are inversely regulated by hypertrophy and atrophy (Latres et al., 2005). However, unique mechanisms are induced during skeletal muscle atrophy, which have been shown to mediate a large part of the phenotypic changes seen during cachexia; these mechanisms involve a significant increase in protein degradation and turnover. Furthermore, distinct transcriptional pathways are activated, and these are not necessarily the converse of those seen during hypertrophy (Haddad, Roy, Zhong, Edgerton, & Baldwin, 2003; Jagoe, Lecker, Gomes, & Goldberg, 2002; Lecker et al., 2004). The stimulation of proteolysis observed during atrophy was shown to occur at least in part due to an activation of the ubiquitin-proteasome pathway (Jagoe et al., 2002). The addition of ubiquitin to a protein substrate has come to be recognized as a regulated signaling process. Three distinct enzymatic components are required, an E1 ubiquitin-activating enzyme, an E2 ubiquitin-conjugating enzyme, and an E3 ubiquitinligating enzyme (Hershko & Ciechanover, 1998). The E3 ubiquitin ligases are the components which confer substrate specicity. Several hundred distinct E3s have been identied, and it is likely that each

modulates the ubiquitination of a distinct set of substrates. Thus, the regulation of ubiquitination can be part of a coordinated signaling pathway, analagous to phosphorylation, in which key pathways might be activated by the enhanced proteolysis of a key inhibitor protein, or in which pathways might be inactivated via the degradation of an activating enzyme. The involvement of the ubiquitin-proteasome pathway in skeletal muscle atrophy had been wellestablished: rates of protein breakdown increase during atrophy; inhibition of the proteasome blocks these increases (Tawa, Odessey, & Goldberg, 1997); the amount of polyubiquitin conjugation per total protein measured increases during atrophy (Lecker et al., 1999); mRNA levels of genes, which encode distinct components of the ubiquitin pathway increase during atrophy (Jagoe et al., 2002; Lecker et al., 2004). Differential expression screening studies, designed to identify markers of the atrophy process, identied two genes whose expression increased signicantly in multiple models of skeletal muscle atrophy: for Muscle Ring Finger1 (MuRF1) (Bodine, Latres, et al., 2001) and for Muscle Atrophy F-box (MAFbx) (Bodine, Latres, et al., 2001) also called Atrogin-1 (Gomes, Lecker, Jagoe, Navon, & Goldberg, 2001). Both MuRF1 and MAFbx/Atrogin were shown to encode E3 ubiquitin ligases (Bodine, Latres, et al., 2001). Expression of MuRF1 and MAFbx is stimulated when the nerve innervating a muscle is cut, thus resulting in paralysis and severe atrophy; these genes are also upregulated by simple immobilization of the muscle or by treatment with a glucocorticoid, which causes muscle atrophy (Bodine, Latres, et al., 2001). In all, 13 distinct models of skeletal muscle atrophy have shown to result in an increase of MAFbx/Atrogin and MuRF1 (Bodine, Latres, et al., 2001; Dehoux, van Beneden, Fernandez-Celemin, Lause, & Thissen, 2003; DeRuisseau et al., 2005; Gomes et al., 2001; Li, Chen, Li, & Reid, 2003; Latres et al., 2005). In the case of sepsis-induced atrophy, both MuRF1 and MAFbx were upregulated several-fold, and this upregulation could be blocked by a pharmacologic inhibitor of glucocorticoids (Wray, Mammen, Hershko, & Hasselgren, 2003), suggesting a distinct mechanism by which sepsis-induces atrophy: through activation of glucocorticoid signaling. MuRF1 encodes a protein which contains three domains: a RING-nger domain (Borden & Freemont,

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1996), which is required for ubiquitin-ligase activity (Kamura et al., 1999); a B-box, whose function is unclear, and a coiled-coil domain, which may be required for the formation of heterodimers between MuRF1 and a related protein, MuRF2 (Centner et al., 2001). Proteins which have these three domains have been called RBCC proteins (for RING, B-box, coiled-coil domain) (Saurin, Borden, Boddy, & Freemont, 1996) or TRIM proteins (for tripartite motif) (Reymond et al., 2001). MuRF1 has been demonstrated to have ubiquitin-ligase activity, which depends on the presence of the RING domain for that activity (Bodine, Latres, et al., 2001). As for substrates, it was recently shown that MuRF1 could induce the ubiquitination of the cardiac form of TroponinI (Kedar et al., 2004), indicating that MuRF1 may act by degrading components of the contractile apparatus. Also suggesting that possibility is that MuRF1 has been shown to bind to the myobrillar protein titin, at the M line (Centner et al., 2001; McElhinny, Kakinuma, Sorimachi, Labeit, & Gregorio, 2002; Pizon et al., 2002). Overexpression of MuRF1 results in the disruption of the subdomain of titin that binds MuRF1, suggesting that MuRF1 may play a role in titin turnover (McElhinny et al., 2002). MuRF1 has also been demonstrated to be in the nucleus, and indications that it interacts with transcription-regulating elements such as GMEB-1 suggest a potential role for MuRF1 in modulating transcription (McElhinny et al., 2002). This has not yet been demonstrated, however. MAFbx/Atrogin-1 contains an F-box domain, a characteristic motif seen in a family of E3 ubiquitin ligases called SCFs (for Skp1, Cullin, F-box) (Jackson & Eldridge, 2002). F-box containing E3 ligases usually bind a substrate only after that substrate has rst been post-translationally modied, for example by phosphorylation (Jackson & Eldridge, 2002). This suggests the possibility of a signaling pathway in which a potential substrate is rst phosphorylated as a response to an atrophy-induced stimulus, and then degraded via MAFbx. Recently, substrates have been suggested for MAFbx, including MyoD (Tintignac et al., 2005) and calcineurin (Li et al., 2004). However, it has not yet been demonstrated if either protein is ubiquitinated by MAFbx in skeletal muscle or during atrophy conditions. Mice which are null for MuRF1 (MuRF1/) and mice are null for MAFbx (MAFbx/) appear

phenotypically normal. However, under atrophy conditions, signicantly less muscle mass is lost in either MuRF1/ or MAFbx/ animals in comparison to control littermates (Bodine, Latres, et al., 2001). This nding demonstrated for the rst time that inhibition of discrete ubiquitin ligases could modulate the amount of muscle lost after an atrophy-inducing stimulus. Therefore, MuRF1 or MAFbx may constitute targets for pharmacologic intervention. They may also serve as early markers of skeletal muscle atrophy, aiding in the diagnosis of muscle disease. There are probably additional E3s, which play important roles in skeletal muscle atrophy. For example, a protein called E3-alphaII was shown to be enriched in skeletal muscle, and its expression is positively regulated by proinammatory cytokines, which can induce skeletal muscle atrophy. During progression of cancer cachexia, E3-alphaII mRNA levels were induced, accompanied by an increase in protein ubiquitination (Kwak et al., 2004). Whether loss of E3-alphaII in any way perturbs the course of muscle atrophy remains to be established; however, it may be important downstream of breakdown of the contractile apparatus, because it has been implicated as an N-end rule ubiquitin ligase, which would presumably be necessary to break down contractile apparatus proteins clipped by other proteases (Kwak et al., 2004).

5. Akt inhibition of FOXO transcription factors blocks upregulation of MuRF1 and MAFbx Studies of differentiated myotube cultures demonstrated that treatment of myotubes with the cachectic glucocorticoid dexamethasone promotes enhanced protein breakdown and increased expression of genes broadly involved in the ubiquitin-proteasome proteolytic pathway (Du, Mitch, Wang, & Price, 2000; Hong & Forsberg, 1995; Wang, Luo, Wang, & Hasselgren, 1998). More recent studies showed that in vitro treatment of myotubes with dexamethasone induces atrophy, accompanied by the specic increased expression of MAFbx and MuRF1 (Sandri et al., 2004; Stitt et al., 2004). The upregulation of MAFbx and MuRF1 was antagonized by simultaneous treatment with IGF-1 (Sacheck, Ohtsuka, McLary, & Goldberg, 2004; Sandri et al., 2004; Stitt et al., 2004), acting through the PI3K/Akt pathway (Sandri et al.,

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2004; Stitt et al., 2004); this nding demonstrated a novel role for Aktin addition to stimulating skeletal muscle hypertrophy, Akt stimulation could dominantly inhibit the induction of atrophy signaling (Fig. 1). Similarly, MuRF1 and MAFbx were activated in a separate model of atrophy, diabetes, and here too IGF-1 blocked the transcriptional upregulation (Lee et al., 2004). Genetic activation of Akt was shown to be sufcient to block the atrophy-associated increases in MAFbx and MuRF1 transcription (Stitt et al., 2004). The mechanism by which Akt inhibited MAFbx and MuRF1 upregulation was demonstrated to involve the FOXO family of transcription factors (Lee et al., 2004; Sandri et al., 2004; Stitt et al., 2004). In myotubes, FOXO transcription factors are excluded from the nucleus when phosphorylated by Akt, and translocate to the nucleus upon dephosphorylation. The translocation and activity of FOXO transcription factors is required for upregulation of MuRF1 and MAFbxin the case of FOXO3, activation was demonstrated to be sufcient to induce atrophy (Sandri et al., 2004), a nding, which was subsequently supported by the transgenic expression of FOXO1, which resulted in atrophic phenotype (Kamei et al., 2004). As a caveat, it should be noted that an earlier study showed that upregulation of IGF-1 was not sufcient to block atrophy (Criswell et al., 1998), whereas a distinct study showed overexpression of IGF-1 was only partially effective (Alzghoul, Gerrard, Watkins, & Hannon, 2004). Therefore, while the experiments with Akt demonstrate the capacity to block atrophy signaling, it has not yet been denitively shown that agents which can activate Akt, such as IGF-1, can be delivered systemically in such a way as to be 100% effective.

stream of Akt, at the level of mTOR, could also block the majority of changes induced by IGF-1, including the inverse regulation of atrophy-stimulated genes (Latres et al., 2004). It was further shown that the requirement of mTOR signaling did not involve phosphorylation of the FOXO transcription factors, since treatment with rapamycin did not perturb FOXO translocation (Latres et al., 2004). Thus, it seems that there may be multiple checkpoints of atrophy signaling downstream of PI3K/Akt activation (Fig. 1). However, it is important to point out that mTOR signaling was not studied in the context of a simultaneous atrophy and hypertrophy signalsmerely that blockade of mTOR inhibited the transcriptional changes induced by IGF-1 (including genes inversely regulated by dexamethasone). Thus, it remains to be seen if mTOR is required for the dominant inhibition of dexamethasone-induced transcriptional changes by IGF-1.

7. Triggers of atrophy: the NF- B pathway and p38 Several cytokines have been shown to induce muscle wasting, most notably TNF , a pro-inammatory secreted cytokine that was originally called cachectin (Argiles & Lopez-Soriano, 1999; Beutler, Mahoney, Le Trang, Pekala, & Cerami, 1985; Tisdale, 1997). TNF levels are elevated in the circulations of patients with cancer cachexia, contributing to negative nitrogen balance (Argiles & Lopez-Soriano, 1999). TNF binding to its receptor induces the activation of the Rel/NF- B (NF- B) family of transcription factors (von Haehling, Genth-Zotz, Anker, & Volk, 2002). NF- B activation was shown to be required for cytokine-induced loss of skeletal muscle proteins (Ladner, Caligiuri, & Guttridge, 2003). Since NF- B in muscle is activated by disuse (Hunter et al., 2002) or sepsis (Penner, Gang, Wray, Fischer, & Hasselgren, 2001), it might play a role in the pathogenesis of these conditions. Consistent with a role for a requisite role of NF- B in atrophy, in vitro blockade inhibits protein loss in C2C12 myotubes (Li & Reid, 2000). Also, consistent with a role for a requisite role of NF- B in atrophy, treatment with TNF- , which induces NF- B signaling, attenuates insulinstimulated protein synthesis (Williamson, Kimball, & Jefferson, 2005). In cells of the immune and inamma-

6. mTOR blocks upregulation of MuRF1 and MAFbx A second, FOXO-independent, anti-atrophy checkpoint downstream of Akt activation was recently demonstrated, by isolating a set of genes regulated by dexamethasone and inversely regulated by IGF-1 (Latres et al., 2004). The genes, which were regulated by IGF-1 in skeletal muscle could be blocked by inhibitors of PI3K, consistent with the previous work demonstrating a requisite role for the PI3K/Akt/FOXO pathway. However, it was shown that inhibition down-

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tory systems, NF- B was demonstrated to be a central integration site for proinammatory signals and a regulator of related target genes. NF- B activation in these cells directly increases the production of cytokines, demonstrating the presence of a feed-forward system. Studies in cultured C2C12 muscle cells suggested that TNF inhibits myocyte differentiation through NF- B activation (Guttridge, Mayo, Madrid, Wang, & Baldwin, 2000; Ladner et al., 2003; Langen, Schols, Kelders, Wouters, & Janssen-Heininger, 2001). The TNF -inhibition of myogenesis was postulated to inhibit the ability of muscle precursor, or satellite, cells to be recruited into the muscle, further enhancing the atrophic effect (Guttridge et al., 2000). A recent paper demonstrated the loss and dysfunction of satellite cells during atrophy, although no link to NF- B signaling was made in that paper (Mitchell & Pavlath, 2004). Activation of NF- B is controlled by the I B kinase complex (IKK). Upon phosphorylation by IKK, I B is ubiquitinated and targeted to the proteasome for degradation, resulting in the activation of NF- B (Yaron et al., 1998). In a recent study, the NF- B pathway was activated or inhibited selectively in the skeletal muscle of transgenic mice, through the muscle-specic expression of either constitutively active IKK or a dominant inhibitory form of I B (Cai et al., 2004). These mice were referred to as MIKK (for muscle specic expression of IKK, which results in activation of the NF- B in the transgenic animals) or MISR (for muscle specic super-repressor, since expression of a dominant negative form of I B represses NF- B activity) (Cai et al., 2004). Activation of the NF- B pathway was demonstrated to be sufcient to induce signicant atrophy, as measured by increases of amino acid excretion and tyrosine turnover in isolated muscles (Cai et al., 2004). The expression of the ubiquitin-ligase MuRF1, but not MAFbx, was upregulated in the MIKK skeletal muscle; this nding provided the rst functional dissection of MuRF1 and MAFbx signaling (Cai et al., 2004). A distinct in vitro study demonstrated that overexpression of I B could block loss of myosin in TNF treated C2C12 myotubes (Ladner et al., 2003). When MIKK mice were crossed into a MuRF1 null background, there was a signicant reduction in muscle loss, demonstrating that transcriptional activation of MuRF1 by NF-kB is a requisite step in NF- B-induced atrophy. Given this data, a linear IKK /NF- B/MuRF1

signaling pathway was proposed (Fig. 1) in which atrophic stimuli, which results in activation of NF- B, thereby induces atrophy in part through the transcriptional upregulation of MuRF1 (Cai et al., 2004). A distinct study, using a knockout of the p105/p50 NF-kB1 gene, demonstrated that there was less atrophy in NF- B1(/) mice as well as a blockade of the ber-type switching associated with atrophy (Hunter & Kandarian, 2004). Also, it was shown that induction of proteasome expression could be attenuated by inhibiting NF- B activity (Wyke, Russel, & Tisdale, 2004), giving further credence to the notion that inhibition of NF- B signaling may be a fruitful mechanism to ameliorate skeletal muscle atrophy. It was noteworthy that MAFbx/Atrogin-1 was not perturbed upon NF- B activation. That nding demonstrated that MAFbx upregulation was not required for NF- B-induced muscle loss. However, given the multiple physiologic settings which do result in MAFbx/Atrogin upregulation, the implication was that a second, parallel pathway, distinct from NF- B, is usually induced during atrophy (Fig. 1). The trigger for upregulation of MAFbx has recently been determined to be p38 (Li et al., 2005). It was shown that TNF acts to stimulate expression of MAFbx, and that this upregulation could be blocked by pharmacologic inhibitors of p38 (Li et al., 2005) (Fig 1). Whether or not p38 has any cross-effect on MuRF1 upregulation, or on the NF- B pathway, has yet to be determined.

8. Conclusion A considerable amount of recent progress has been made in the understanding of the signaling pathways which mediate skeletal muscle hypertrophy and atrophy. Whereas it was appreciated many years ago that hypertrophy comes about via an increase in the rate of protein synthesis, and atrophy through an increase in protein degradation, only now can specic signaling pathways be drawn, since molecular mediators of hypertrophy and atrophy in skeletal muscle have only recently begun to be determined. Furthermore, it is only through recent studies that it is understood that hypertrophy pathways are dominant over the induction of atrophy mediators. These ndings help to give hope that novel drug targets may be found to block skeletal

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muscle atrophy seen in a variety of clinical conditions, from the cachexia of AIDS, sepsis and cancer, to the gradual loss of muscle mass observed during normal aging.

Acknowledgements Thanks to Dr. G.D. Yancopoulos, Dr. P.R.Vagelos, Dr. L.S. Schleifer as well as the rest of the Regeneron Community, for their enthusiastic support and input. Thank you for Trevor Stitt for comments on this manuscript. Sincere apologies to scientic colleagues whose work was omitted from this review due to space constraints.

References
Alzghoul, M. B., Gerrard, D., Watkins, B. A., & Hannon, K. (2004). Ectopic expression of IGF-I and Shh by skeletal muscle inhibits disuse-mediated skeletal muscle atrophy and bone osteopenia in vivo. FASEB J., 18, 221223. Argiles, J. M., & Lopez-Soriano, F. J. (1999). The role of cytokines in cancer cachexia. Med. Res. Rev., 19, 223248. Beals, C. R., Sheridan, C. M., Turck, C. W., Gardner, P., & Crabtree, G. R. (1997). Nuclear export of NF-ATc enhanced by glycogen synthase kinase-3. Science, 275, 19301934. Beutler, B., Mahoney, J., Le Trang, N., Pekala, P., & Cerami, A. (1985). Purication of cachectin, a lipoprotein lipasesuppressing hormone secreted by endotoxin-induced RAW 264.7 cells. J. Exp. Med., 161, 984995. Bodine, S. C., Latres, E., Baumhueter, S., Lai, V. K., Nunez, L., Clarke, B. A., et al. (2001). Identication of ubiquitin ligases required for skeletal muscle atrophy. Science, 294, 17041708. Bodine, S. C., Stitt, T. N., Gonzalez, M., Kline, W. O., Stover, G. L., Bauerlein, R., et al. (2001). Akt/mTOR pathway is a crucial regulator of skeletal muscle hypertrophy and can prevent muscle atrophy in vivo. Nat. Cell. Biol., 3, 10141019. Bohni, R., Riesgo-Escovar, J., Oldham, S., Brogiolo, W., Stocker, H., Andruss, B. F., et al. (1999). Autonomous control of cell and organ size by CHICO, a Drosophila homolog of vertebrate IRS1-4. Cell, 97, 865875. Borden, K. L., & Freemont, P. S. (1996). The RING nger domain: A recent example of a sequence-structure family. Curr. Opin. Struct. Biol., 6, 396401. Burnett, P. E., Barrow, R. K., Cohen, N. A., Snyder, S. H., & Sabatini, D. M. (1998). RAFT1 phosphorylation of the translational regulators p70 S6 kinase and 4E-BP1. Proc. Natl. Acad. Sci. U.S.A., 95, 14321437. Cai, D., Frantz, J. D., Tawa, N. E., Jr., Melendez, P. A., Lidov, H. G. W., Hasselgren, P. O., et al. (2004). IKKbeta/NF-kappaB activation causes severe muscle wasting in mice. Cell, 119, 285 298.

Centner, T., Yano, J., Kimura, E., McElhinny, A. S., Pelin, K., Witt, C. C., et al. (2001). Identication of muscle specic ring nger proteins as potential regulators of the titin kinase domain. J. Mol. Biol., 306, 717726. Choi, K. M., McMahon, L. P., & Lawrence, J. C., Jr. (2003). Two motifs in the translational repressor PHAS-I required for efcient phosphorylation by mTOR and recognition by raptor. J. Biol. Chem., M301142200. Coleman, M. E., DeMayo, F., Yin, K. C., Lee, H. M., Geske, R., Montgomery, C., et al. (1995). Myogenic vector expression of insulin-like growth factor I stimulates muscle cell differentiation and myober hypertrophy in transgenic mice. J. Biol. Chem., 270, 1210912116. Criswell, D. S., Booth, F. W., DeMayo, F., Schwartz, R. J., Gordon, S. E., & Fiorotto, M. L. (1998). Overexpression of IGF-I in skeletal muscle of transgenic mice does not prevent unloading-induced atrophy. Am. J. Physiol., 275, E373E379. Cross, D. A., Alessi, D. R., Cohen, P., Andjelkovich, M., & Hemmings, B. A. (1995). Inhibition of glycogen synthase kinase-3 by insulin mediated by protein kinase B. Nature, 378, 785789. Dehoux, M. J. M., van Beneden, R. P., Fernandez-Celemin, L., Lause, P. L., & Thissen, J.-P. M. (2003). Induction of MafBx and Murf ubiquitin ligase mRNAs in rat skeletal muscle after LPS injection. FEBS Lett., 544, 214217. DeRuisseau, K. C., Kavazis, A. N., Deering, M. A., Falk, D. J., Van Gammeren, D., Yimlamai, T., Ordway, G. A., & Powers, S. K. (2005). Mechanical ventilation induces alterations of the ubiquitin-proteasome pathway in the diaphragm. J. Appl. Physiol., 98, 13141321, Epub 2004 Nov 19. DeVol, D. L., Rotwein, P., Sadow, J. L., Novakofski, J., & Bechtel, P. J. (1990). Activation of insulin-like growth factor gene expression during work-induced skeletal muscle growth. Am. J. Physiol., 259, E89E95. Diaz-Benjumea, F. J., & Cohen, S. M. (1994). Wingless acts through the shaggy/zeste-white 3 kinase to direct dorsal-ventral axis formation in the Drosophila leg. Development, 120, 16611670. Du, J., Mitch, W. E., Wang, X., & Price, S. R. (2000). Glucocorticoids induce proteasome C3 subunit expression in L6 muscle cells by opposing the suppression of its transcription by NF-kappa B. J. Biol. Chem., 275, 1966119666. Gomes, M. D., Lecker, S. H., Jagoe, R. T., Navon, A., & Goldberg, A. L. (2001). Atrogin-1, a muscle-specic F-box protein highly expressed during muscle atrophy. Proc. Natl. Acad. Sci. U.S.A., 98, 1444014445. Guttridge, D. C., Mayo, M. W., Madrid, L. V., Wang, C. Y., & Baldwin, A. S., Jr. (2000). NF-kappaB-induced loss of MyoD messenger RNA: Possible role in muscle decay and cachexia. Science, 289, 23632366. Haddad, F., Roy, R. R., Zhong, H., Edgerton, V. R., & Baldwin, K. M. (2003). Atrophy responses to muscle inactivity II: Molecular markers of protein decits. J. Appl. Physiol., 25, 25. Hannan, K. M., Thomas, G., & Pearson, R. B. (2003). Activation of S6K1 (p70 ribosomal protein S6 kinase 1) requires an initial calcium-dependent priming event involving formation of a highmolecular-mass signalling complex. Biochem. J., 370, 469477. Haq, S., Choukroun, G., Kang, Z. B., Ranu, H., Matsui, T., Rosenzweig, A., et al. (2000). Glycogen synthase kinase-3{beta} is a

1982

D.J. Glass / The International Journal of Biochemistry & Cell Biology 37 (2005) 19741984 Kubica, N., Bolster, D. R., Farrell, P. A., Kimball, S. R., & Jefferson, L. S. (2005). Resistance exercise increases muscle protein synthesis and translation of eukaryotic initiation factor 2B{epsilon} mRNA in a mammalian target of rapamycin-dependent manner. J. Biol. Chem., 280, 75707580. Kwak, K. S., Zhou, X., Solomon, V., Baracos, V. E., Davis, J., Bannon, A. W., et al. (2004). Regulation of protein catabolism by muscle-specic and cytokine-inducible ubiquitin ligase E3alphaII during cancer cachexia. Cancer Res., 64, 81938198. Ladner, K. J., Caligiuri, M. A., & Guttridge, D. C. (2003). Tumor necrosis factor-regulated biphasic activation of NF-kappa B is required for cytokine-induced loss of skeletal muscle gene products. J. Biol. Chem., 278, 22942303. Lai, K.-M., Gonzalez, M., Poueymirou, W. T., Kline, W. O., Na, E., Zlotchenko, E., et al. (2004). Conditional activation of akt in adult skeletal muscle induces rapid hypertrophy. Mol. Cell. Biol., 24, 92959304. Langen, R. C., Schols, A. M., Kelders, M. C., Wouters, E. F., & Janssen-Heininger, Y. M. (2001). Inammatory cytokines inhibit myogenic differentiation through activation of nuclear factorkappaB. FASEB J., 15, 11691180. Latres, E., Amini, A. R., Amini, A. A., Grifths, J., Martin, F. J., Wei, Y., et al. (2005). IGF-1 inversely regulates atrophy-induced genes via the PI3K/Akt/mTOR pathway. J. Biol. Chem., 280, 27372744. Lecker, S. H., Jagoe, R. T., Gilbert, A., Gomes, M., Baracos, V., Bailey, J., et al. (2004). Multiple types of skeletal muscle atrophy involve a common program of changes in gene expression. FASEB J., 18, 3951. Lecker, S. H., Solomon, V., Price, S. R., Kwon, Y. T., Mitch, W. E., & Goldberg, A. L. (1999). Ubiquitin conjugation by the N-end rule pathway and mRNAs for its components increase in muscles of diabetic rats. J. Clin. Invest., 104, 14111420. Lee, S. W., Dai, G., Hu, Z., Wang, X., Du, J., & Mitch, W. E. (2004). Regulation of muscle protein degradation: Coordinated control of apoptotic and ubiquitin-proteasome systems by phosphatidylinositol 3 kinase. J. Am. Soc. Nephrol., 15, 15371545. Leevers, S. J., Weinkove, D., MacDougall, L. K., Hafen, E., & Watereld, M. D. (1996). The Drosophila phosphoinositide 3-kinase Dp110 promotes cell growth. EMBO J., 15, 65846594. Li, H. H., Kedar, V., Zhang, C., McDonough, H., Arya, R., Wang, D. Z., et al. (2004). Atrogin-1/muscle atrophy F-box inhibits calcineurin-dependent cardiac hypertrophy by participating in an SCF ubiquitin ligase complex. J. Clin. Invest., 114, 1058 1071. Li, Y.-P., Chen, Y., John, J., Moylan, J., Jin, B., Mann, D. L., et al. (2005). TNF-{alpha} acts via p38 MAPK to stimulate expression of the ubiquitin ligase atrogin1/MAFbx in skeletal muscle. FASEB J., 19, 362370. Li, Y.-P., Chen, Y., Li, A. S., & Reid, M. B. (2003). Hydrogen peroxide stimulates ubiquitin conjugating activity and expression of genes for specic E2 and E3 proteins in skeletal muscle myotubes. Am. J. Physiol. Cell. Physiol., 285, C806C812. Li, Y. P., & Reid, M. B. (2000). NF-kappaB mediates the protein loss induced by TNF-alpha in differentiated skeletal muscle myotubes. Am. J. Physiol. Regul. Integr. Comp. Physiol., 279, R1165R1170.

negative regulator of cardiomyocyte hypertrophy. J. Cell. Biol., 151, 117130. Hara, K., Maruki, Y., Long, X., Yoshino, K., Oshiro, N., Hidayat, S., et al. (2002). Raptor, a binding partner of target of rapamycin (TOR), mediates TOR action. Cell, 110, 177189. Hara, K., Yonezawa, K., Kozlowski, M. T., Sugimoto, T., Andrabi, K., Weng, Q. P., et al. (1997). Regulation of eIF-4E BP1 phosphorylation by mTOR. J. Biol. Chem., 272, 2645726463. Hara, K., Yonezawa, K., Weng, Q. P., Kozlowski, M. T., Belham, C., & Avruch, J. (1998). Amino acid sufciency and mTOR regulate p70 S6 kinase and eIF-4E BP1 through a common effector mechanism [published erratum appears in J Biol Chem 1998 Aug 21;273(34):22160]. J. Biol. Chem., 273, 14484 14494. Hardt, S. E., & Sadoshima, J. (2002). Glycogen synthase kinase3beta: A novel regulator of cardiac hypertrophy and development. Circ. Res., 90, 155163. Hershko, A., & Ciechanover, A. (1998). The ubiquitin system. Annu. Rev. Biochem., 67, 425427. Hong, D. H., & Forsberg, N. E. (1995). Effects of dexamethasone on protein degradation and protease gene expression in rat L8 myotube cultures. Mol. Cell. Endocrinol., 108, 199 209. Hunter, R. B., & Kandarian, S. C. (2004). Disruption of either the Nfkb1 or the Bcl3 gene inhibits skeletal muscle atrophy. J. Clin. Invest., 114, 15041511. Hunter, R. B., Stevenson, E., Koncarevic, A., Mitchell-Felton, H., Essig, D. A., & Kandarian, S. C. (2002). Activation of an alternative NF-kappaB pathway in skeletal muscle during disuse atrophy. FASEB J., 16, 529538. Inoki, K., Li, Y., Zhu, T., Wu, J., & Guan, K. L. (2002). TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling. Nat. Cell. Biol., 4, 648657. Jackson, P. K., & Eldridge, A. G. (2002). The SCF ubiquitin ligase: An extended look. Mol. Cell., 9, 923925. Jagoe, R. T., Lecker, S. H., Gomes, M., & Goldberg, A. L. (2002). Patterns of gene expression in atrophying skeletal muscles: Response to food deprivation. FASEB J., 16, 16971712. Kamei, Y., Miura, S., Suzuk, M., Kai, Y., Mizukami, J., Taniguchi, T., et al. (2004). Skeletal muscle FOXO1 (FKHR) transgenic mice have less skeletal muscle mass, down-regulated Type I (slow twitch/red muscle) ber genes, and impaired glycemic control. J. Biol. Chem., 279, 41114411123. Kamura, T., Koepp, D. M., Conrad, M. N., Skowyra, D., Moreland, R. J., Iliopoulos, O., et al. (1999). Rbx1, a component of the VHL tumor suppressor complex and SCF ubiquitin ligase [see comments]. Science, 284, 657661. Kawano, Y., & Kypta, R. (2003). Secreted antagonists of the Wnt signalling pathway. J. Cell. Sci., 116, 26272634. Kedar, V., McDonough, H., Arya, R., Li, H. H., Rockman, H. A., & Patterson, C. (2004). Muscle-specic RING nger 1 is a bona de ubiquitin ligase that degrades cardiac troponin I. Proc. Natl. Acad. Sci. U. S. A., 52, 1813518140, Epub 2004 Dec 15. Kim do, H., Sarbassov dos, D., Ali, S. M., King, J. E., Latek, R. R., Erdjument-Bromage, H., et al. (2002). mTOR interacts with raptor to form a nutrient-sensitive complex that signals to the cell growth machinery. Cell, 110, 163175.

D.J. Glass / The International Journal of Biochemistry & Cell Biology 37 (2005) 19741984 McElhinny, A. S., Kakinuma, K., Sorimachi, H., Labeit, S., & Gregorio, C. C. (2002). Muscle-specic RING nger-1 interacts with titin to regulate sarcomeric M-line and thick lament structure and may have nuclear functions via its interaction with glucocorticoid modulatory element binding protein-1. J. Cell. Biol., 157, 125136. Mitchell, P. O., & Pavlath, G. K. (2004). Skeletal muscle atrophy leads to loss and dysfunction of muscle precursor cells. Am. J. Physiol. Cell. Physiol., 287, C1753C1762. Montagne, J., Stewart, M. J., Stocker, H., Hafen, E., Kozma, S. C., & Thomas, G. (1999). Drosophila S6 kinase: A regulator of cell size [see comments]. Science, 285, 21262129. Musaro, A., McCullagh, K., Paul, A., Houghton, L., Dobrowolny, G., Molinaro, M., et al. (2001). Localized Igf-1 transgene expression sustains hypertrophy and regeneration in senescent skeletal muscle. Nat. Genet., 27, 195200. Ohanna, M., Sobering, A. K., Lapointe, T., Lorenzo, L., Praud, C., Petroulakis, E., et al. (2005). Atrophy of S6K1/ skeletal muscle cells reveals distinct mTOR effectors for cell cycle and size control. Nat. Cell. Biol., 7, 286. Pallafacchina, G., Calabria, E., Serrano, A. L., Kalhovde, J. M., & Schiafno, S. (2002). A protein kinase B-dependent and rapamycin- sensitive pathway controls skeletal muscle growth but not ber type specication. Proc. Natl. Acad. Sci. U.S.A., 25, 25. Penner, C. G., Gang, G., Wray, C., Fischer, J. E., & Hasselgren, P. O. (2001). The transcription factors NF-kB and AP-1 are differentially regulated in skeletal muscle during sepsis. Biochem. Biophys. Res. Commun., 281, 13311336. Pizon, V., Iakovenko, A., Van Der Ven, P. F., Kelly, R., Fatu, C., Furst, D. O., et al. (2002). Transient association of titin and myosin with microtubules in nascent myobrils directed by the MURF2 RING-nger protein. J. Cell. Sci., 115, 44694482. Proud, C. G. (2004). mTOR-mediated regulation of translation factors by amino acids. Biochem. Biophys. Res. Commun., 313, 429436. Pullen, N., Dennis, P. B., Andjelkovic, M., Dufner, A., Kozma, S. C., Hemmings, B. A., et al. (1998). Phosphorylation and activation of p70s6k by PDK1. Science, 279, 707710. Reymond, A., Meroni, G., Fantozzi, A., Merla, G., Cairo, S., Luzi, L., et al. (2001). The tripartite motif family identies cell compartments. EMBO J., 20, 21402151. Rochat, A., Fernandez, A., Vandromme, M., Moles, J. P., Bouschet, T. G. C., & Lamb, N. J. (2004). Insulin and wnt1 pathways cooperate to induce reserve cell activation in differentiation and myotube hypertrophy. Mol. Biol. Cell., 15, 45444555. Rommel, C., Bodine, S. C., Clarke, B. A., Rossman, R., Nunez, L., Stitt, T. N., et al. (2001). Mediation of IGF-1induced skeletal myotube hypertrophy by PI(3)K/Akt/mTOR and PI(3)K/Akt/GSK3 pathways. Nat. Cell. Biol., 3, 109113. Rommel, C., Clarke, B. A., Zimmermann, S., Nunez, L., Rossman, R., Reid, K., et al. (1999). Differentiation stage-specic inhibition of the raf-MEK-ERK pathway by Akt. Science, 286, 17381741. Sacheck, J. M., Ohtsuka, A., McLary, S. C., & Goldberg, A. L. (2004). IGF-1 stimulates muscle growth by suppressing protein breakdown and expression of atrophy-related ubiquitin-ligases,

1983

atrogin-1 and MuRF1. Am. J. Physiol. Endocrinol. Metab., 287, E591E601. Saitoh, M., Pullen, N., Brennan, P., Cantrell, D., Dennis, P. B., & Thomas, G. (2002). Regulation of an activated S6 kinase 1 variant reveals a novel mammalian target of rapamycin phosphorylation site. J. Biol. Chem., 277, 2010420112. Sandri, M., Sandri, C., Gilbert, A., Skurk, C., Calabria, E., Picard, A., et al. (2004). Foxo transcription factors induce the atrophyrelated ubiquitin ligase atrogin-1 and cause skeletal muscle atrophy. Cell, 117, 399412. Saurin, A. J., Borden, K. L., Boddy, M. N., & Freemont, P. S. (1996). Does this have a familiar RING? Trends Biochem. Sci., 21, 208214. Schalm, S. S., Fingar, D. C., Sabatini, D. M., & Blenis, J. (2003). TOS motif-mediated raptor binding regulates 4E-BP1 multisite phosphorylation and function. Curr. Biol., 13, 797806. Stitt, T. N., Drujan, D., Clarke, B. A., Panaro, F. J., Timofeyva, Y., Kline, W. O., et al. (2004). The IGF-1/PI3K/Akt pathway prevents expression of muscle atrophy-induced ubiquitin ligases by inhibiting FOXO transcription factors. Mol. Cell., 14, 395403. Sugita, H., Kaneki, M., Sugita, M., Yasukawa, T., Yasuhara, S., & Martyn, J. A. (2005). Burn injury impairs insulinstimulated Akt/PKB activation in skeletal muscle. Am. J. Physiol. Endocrinol. Metab., 288, E585E591. Svanberg, E., Frost, R. A., Lang, C. H., Isgaard, J., Jefferson, L. S., Kimball, S. R., et al. (2000). IGF-I/IGFBP-3 binary complex modulates sepsis-induced inhibition of protein synthesis in skeletal muscle. Am. J. Physiol. Endocrinol. Metab., 279, E1145E1158. Tawa, N. E., Jr., Odessey, R., & Goldberg, A. L. (1997). Inhibitors of the proteasome reduce the accelerated proteolysis in atrophying rat skeletal muscles. J. Clin. Invest., 100, 197203. Tee, A. R., Fingar, D. C., Manning, B. D., Kwiatkowski, D. J., Cantley, L. C., & Blenis, J. (2002). Tuberous sclerosis complex-1 and -2 gene products function together to inhibit mammalian target of rapamycin (mTOR)-mediated downstream signalling. Proc. Natl. Acad. Sci. U.S.A., 99, 1357113576. Tintignac, L. A., Lagirand, J., Batonnet, S., Sirri, V., Leibovitch, M. P., & Leibovitch, S. A. (2005). Degradation of MyoD mediated by the SCF (MAFbx) ubiquitin ligase. J. Biol. Chem., 280(4), 28472856, Epub 2004 Nov 5. Tisdale, M. J. (1997). Biology of cachexia. J. Natl. Cancer Inst., 89, 17631773. Vandenburgh, H. H., Karlisch, P., Shansky, J., & Feldstein, R. (1991). Insulin and IGF-I induce pronounced hypertrophy of skeletal myobers in tissue culture. Am. J. Physiol., 260, C475 C484. Veeman, M. T., Axelrod, J. D., & Moon, R. T. (2003). A second canon. Functions and mechanisms of beta-catenin-independent Wnt signalling. Dev. Cell., 5, 367377. von Haehling, S., Genth-Zotz, S., Anker, S. D., & Volk, H. D. (2002). Cachexia: A therapeutic approach beyond cytokine antagonism. Int. J. Cardiol., 85, 173183. Vyas, D. R., Spangenburg, E. E., Abraha, T. W., Childs, T. E., & Booth, F. W. (2002). GSK-3beta negatively regulates skeletal myotube hypertrophy. Am. J. Physiol. Cell. Physiol., 283, C545C551.

1984

D.J. Glass / The International Journal of Biochemistry & Cell Biology 37 (2005) 19741984 Wyke, S. M., Russel, S. T., & Tisdale, M. J. (2004). Induction of proteasome expression in skeletal muscle is attenuated by inhibitors of NF-kappaB activation. Br. J. Cancer, 91, 1742 1750. Yaron, A., Hatzubai, A., Davis, M., Lavon, I., Amit, S., Manning, A. M., et al. (1998). Identication of the receptor component of the IkappaBalpha-ubiquitin ligase. Nature, 396, 590 594. Zhang, H., Stallock, J. P., Ng, J. C., Reinhard, C., & Neufeld, T. P. (2000). Regulation of cellular growth by the drosophila target of rapamycin dTOR [in process citation]. Genes Dev., 14, 27122724.

Wang, L., Luo, G. J., Wang, J. J., & Hasselgren, P. O. (1998). Dexamethasone stimulates proteasome- and calcium-dependent proteolysis in cultured L6 myotubes. Shock, 10, 298306. Williamson, D. L., Kimball, S. R., & Jefferson, L. S. (2005). Acute treatment with TNF-{alpha} attenuates insulin-stimulated protein synthesis in cultures of C2C12 myotubes through a MEK1-sensitive mechanism. Am. J. Physiol. Endocrinol. Metab., E95E104. Wray, C. J., Mammen, J. M., Hershko, D. D., & Hasselgren, P. O. (2003). Sepsis upregulates the gene expression of multiple ubiquitin ligases in skeletal muscle. Int. J. Biochem. Cell. Biol., 35, 698705.

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